Enhanced repair of articular cartilage defects in vivo by transplanted chondrocytes overexpressing insulin-like growth factor I (IGF-I)

Abstract

Traumatic articular cartilage lesions have a limited capacity to heal. We tested the hypothesis that overexpression of a human insulin-like growth factor I (IGF-I) cDNA by transplanted articular chondrocytes enhances the repair of fullthickness (osteochondral) cartilage defects in vivo. Lapine articular chondrocytes were transfected with expression plasmid vectors containing the cDNA for the Escherichia coli lacZ gene or the human IGF-I gene and were encapsulated in alginate. The expression patterns of the transgenes in these implants were monitored in vitro for 36 days. Transfected allogeneic chondrocytes in alginate were transplanted into osteochondral defects in the trochlear groove of rabbits. At three and 14 weeks, the quality of articular cartilage repair was evaluated qualitatively and quantitatively. In vitro, IGF-I secretion by implants constructed from IGF-I-transfected chondrocytes and alginate was 123.2722.3 ng/10 7 cells/24 h at day 4 post transfection and remained elevated at day 36, the longest time point evaluated. In vivo, transplantation of IGF-I implants improved articular cartilage repair and accelerated the formation of the subchondral bone at both time points compared to lacZ implants. The data indicate that allogeneic chondrocytes, transfected by a nonviral method and cultured in alginate, are able to secrete biologically relevant amounts of IGF-I over a prolonged period of time in vitro. The data further demonstrate that implantation of these composites into deep articular cartilage defects is sufficient to augment cartilage defect repair in vivo. These results suggest that therapeutic growth factor gene delivery using encapsulated and transplanted genetically modified chondrocytes may be applicable to sites of focal articular cartilage damage.

Combination of baculovirus-expressed BMP-2 and rotating-shaft bioreactor culture synergistically enhances cartilage formation

“…2 Another common approach involves the ex vivo gene transduction of autologous cells, followed by immediate encapsulation into a scaffold and implantation. 33 The ex vivo approach minimizes the unwanted immune responses but the cell/scaffold constructs devoid of cartilage ECM may have suboptimal mechanical properties to tolerate the mechanical loading in vivo immediately after implantation, which could impair subsequent tissue integration. 34 In addition, the cells transplanted into full-thickness defects may not remain for long time periods.…”

Innovative Strategies for Treatment of Soft Tissue Injuries in Human and Animal Athletes

“…In addition, these modified cells were applied in collagen gel or organ tissue explants. In vitro delivery of genes for BMP2, IGF-1, and TGF-beta to articular chondroytes has been shown to increase proteoglycan synthesis by the cultured cells (see, e. g., [29,30]). After retroviral overexpression of BMP-7 in mesenchymal stem cells and cell delivery on a polyglycolic acid scaffold a rabbit osteochondral articular cartilage defect showed improved healing [31].…”

Collagen scaffolds for nonviral IGF-1 gene delivery in articular cartilage tissue engineering

“…[1][2][3][4] Prolonged expression of the protein from infected cells, however, is limited in vivo owing to the migration of these cells from the defect site and apoptosis. 5 An alternative approach for incorporating transfected cells for prolonged protein release is a 'substrate-mediated' 6 gene transfer method, in which tissue-engineering scaffolds are used as gene delivery vehicles to seeded cells and/or endogenous cells in vivo.…”

“…[18][19][20][21][22][23] Although studies have shown effective IGF-1 gene transfer to cells using an ex vivo approach for enhancing articular cartilage tissue engineering, 1,4,24 there has not yet been an investigation demonstrating IGF-1 gene transfer to cells using a substrate-mediated nonviral gene transfer approach using collagen scaffolds.…”

“…Both viral 1,3,7 and nonviral 4,[8][9][10][11][12][13] vectors have been employed to provide an elevated release of desired proteins from infected cells for tissue engineering applications. Although viral methods generally have a much higher efficiency of gene transfer, especially for slowly dividing or non-dividing cells, the inherent immunogenicity of viral vectors commends nonviral methods for tissue engineering applications.…”